WO2005096694A2 - Methode de detection, de diagnostic et de pronostic du cancer du poumon faisant appel a trois points temporels - Google Patents

Methode de detection, de diagnostic et de pronostic du cancer du poumon faisant appel a trois points temporels Download PDF

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Publication number
WO2005096694A2
WO2005096694A2 PCT/IB2005/001252 IB2005001252W WO2005096694A2 WO 2005096694 A2 WO2005096694 A2 WO 2005096694A2 IB 2005001252 W IB2005001252 W IB 2005001252W WO 2005096694 A2 WO2005096694 A2 WO 2005096694A2
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Prior art keywords
concentration value
lung tissue
contrast agent
malignancy
region
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PCT/IB2005/001252
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English (en)
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WO2005096694A3 (fr
Inventor
Hadassa Degani
Daphna Weinstein
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Yeda Research And Development Co., Ltd.
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Priority to CA002561168A priority Critical patent/CA2561168A1/fr
Priority to EP05747932A priority patent/EP1743279A4/fr
Priority to US10/593,887 priority patent/US7693320B2/en
Publication of WO2005096694A2 publication Critical patent/WO2005096694A2/fr
Priority to IL178472A priority patent/IL178472A0/en
Publication of WO2005096694A3 publication Critical patent/WO2005096694A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48—Diagnostic techniques
    • A61B6/481—Diagnostic techniques involving the use of contrast agents
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T7/00—Image analysis
    • G06T7/0002—Inspection of images, e.g. flaw detection
    • G06T7/0012—Biomedical image inspection
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06V—IMAGE OR VIDEO RECOGNITION OR UNDERSTANDING
    • G06V20/00—Scenes; Scene-specific elements
    • G06V20/60—Type of objects
    • G06V20/69—Microscopic objects, e.g. biological cells or cellular parts
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T2207/00—Indexing scheme for image analysis or image enhancement
    • G06T2207/30—Subject of image; Context of image processing
    • G06T2207/30004—Biomedical image processing
    • G06T2207/30061—Lung
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T2207/00—Indexing scheme for image analysis or image enhancement
    • G06T2207/30—Subject of image; Context of image processing
    • G06T2207/30004—Biomedical image processing
    • G06T2207/30096—Tumor; Lesion
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06V—IMAGE OR VIDEO RECOGNITION OR UNDERSTANDING
    • G06V2201/00—Indexing scheme relating to image or video recognition or understanding
    • G06V2201/03—Recognition of patterns in medical or anatomical images

Definitions

  • the present application relates to medical imaging devices generally, and to methods, systems, and programs of instructions for the evaluation of potentially malignant tissue based on computed tomography (CT) or other such imaging devices.
  • CT computed tomography
  • Lung cancer represents one of the major public health problems worldwide. It has been estimated that between 1.3 and 2 million people died from lung cancer in the year
  • Non-Small Cell Lung Carcinoma represents 80% of the bronchogenic carcinomas, which include Adenocarcinoma, SCC (Squamous Cell Carcinoma), LCC
  • SCLC Small Cell Lung Cancer
  • Oat Cell Carcinoma comprises the rest of the cases. SCLC is the most aggressive type with a median survival of 2-4 months. Less common types include Sarcoma,
  • Carcinosarcoma Blastoma, Lymphoma, and Neuroendocrine tumors such as Carcinoids
  • diagnostic techniques are the following:
  • CXR Conventional Chest X-Ray
  • CXR may provide information regarding factors such as the size, shape, density and site of the lesion, apart from the existence of pleural effusions, alveolar or interstitial spread, collapse, lymphadenopathy, and rib metastases.
  • An opacity is suspicious for malignancy if it has not calcified, has spiculations, grows rapidly, or is >3 cm in diameter.
  • a lesion that has not grown in two years may be generally considered to be benign.
  • CT Computer Tomography
  • CT is a preferred modality for lung cancer diagnosis and staging.
  • the injection of a contrast agent or material helps differentiate between blood vessels and lymph nodes.
  • CT can offer better evaluation of the tumor's borders, the tumor's relation to neighboring structures, and the involvement of lymph nodes, bones, liver and adrenals.
  • CT low-dose helical CT
  • HRCT - high Resolution CT HRCT - high Resolution CT
  • phase-contrast CT phase-contrast CT.
  • Spiral CT provides higher spatial resolution than a CXR, at the expense however, of greater radiation exposure.
  • the radiation exposure may be greater by 10-100 than that in a CXR, while spiral CT exposes the subject to only 10-20%) the exposure of conventional CT.
  • CT allows scanning of the whole lung during a single breath-hold of 8-25 seconds.
  • enhancement obtained by the contrast material is usually greater in malignant tumors due to the rich vascularity typical of malignant tissue.
  • non- enhancement means no malignancy, although some benign tissues do enhance.
  • CT cardiovascular disease
  • Tumor perfusion has been found to be dependent on tumor size and localization, but not on histology. Furthermore, perfusion CT disclosed blood supply from both pulmonary and/or bronchial vessels in some tumors. In these dynamic studies both the spatial and temporal resolution were high but the scanning was limited to small volumes and short time span in order to minimize radiation hazards.
  • CT detects lesions that are greater than 2 mm, of which 45% are neoplastic.
  • CT is superior to CXR because CT provides staging, volumetric, and density data (higher enhancement and size being more characteristic of malignancy), and evaluation of the best method to obtain a biopsy, including needle localization for biopsy under NATS (Nideo Assisted Thoracoscopic Surgery).
  • NATS Neo Assisted Thoracoscopic Surgery.
  • MRI Magnetic Resonance Imaging
  • DCE dynamic contrast enhanced
  • the response of the vascular physiology to treatment of lung cancer was also assessed by DCE MRI (Hunter G.J., Hamberg L.M., Choi N, Jain R.K., McCloud T, Fischman A.J., Dynamic Tl -Weighted Magnetic Resonance Imaging and Positron Emission Tomography In Patients with Lung Cancer: Correlating Vascular Physiology with Glucose Metabolism, Clin. Cancer Res. 1998 Apr;4 (4):949-55).
  • Values for the extracellular contrast distribution space were 0.321 +/- 0.03 before, 0.289 +/- 0.02 midway through, and 0.195 +/- 0.02 (P ⁇ 0.01) 2 weeks after therapy.
  • the glucose metabolic rate was significantly correlated with the PS product (P ⁇ 0.01) but not with the extracellular contrast distribution space.
  • PET Pulsitron Emission Tomography
  • 18-fluorodeoxyglucose depicts increased glucose metabolism in tumor cells. This served to evaluate the primary tumor as well as regional lymph nodes and distant metastases.
  • Percutaneous needle biopsy, flexible fiberoptic bronchoscopy as well as surgical exploration offer additional diagnostic tools. However, they are characterized by inherent invasiveness. Recent developments include exhalation analysis of certain volatile organic compounds, cytological sputum analysis, immunostaining for hnRNP, A2/B1 or PGP9.5, and polymerase chain reaction-based assays for detecting tumor-specific mutations. Despite the various diagnostic modalities, 10-20%> of patients undergo thoracotomy without prior pathologic diagnosis. The exact treatment regimen depends on precise histological data before treatment and after excision.
  • stage I the survival is 60- 70%
  • stage la even higher the overall survival has not risen lately.
  • the one-year survival rate has increased from 32%> in 1973 to 41% in 1994.
  • the overall five-year survival rate is only 14%>.
  • Concerning lung metastases the prognosis depends on the type of primary -tumor and its biological behavior. For some carcinomas and sarcomas, the five-year survival after lung metastases excision is 25-45% > .
  • SPN sinuen lesion
  • a method, system and computer-readable medium that provide a malignancy classification for a region of lung tissue are disclosed.
  • the classifying operation includes some or all of the following: time points Ti and T 2 measured from a time point T 0 at or near an injection of a contrast agent are set as described below.
  • Ti represents a wash-in time point for malignant lung tissue at which a first concentration value of the injected contrast agent is substantially equal to or near a peak for injected contrast agent concentration in the region of lung tissue.
  • T 2 may be set such that a second concentration value of the injected contrast agent for malignant tissue is less than the first concentration value, and a third concentration value of the injected contrast agent for non-malignant tissue at Ti is less than a fourth concentration value of the injected contrast agent concentration for the non-malignant tissue at T 2 .
  • T may be set such that the second concentration value of the injected contrast agent for malignant tissue is substantially equal to the first concentration value, provided that the first concentration value exceeds a certain threshold value.
  • Patient concentration values of the contrast agent for the area of lung tissue at time points Ti and T 2 are obtained, and a malignancy classification for the region of lung tissue is provided by comparing the obtained sample concentration values with a predetermined malignancy profile. A visual representation of the malignancy classification of the region of lung tissue is outputted.
  • the time points may be set such that the second concentration value is greater than the fourth concentration value.
  • setting of the time points Ti and T 2 may also include calculating concentration values of the injected contrast agent at initial time points Ti and T , finding a maximum intensity for a calibration map comprising a grid with axes K and v, K representing a microvascular permeability value and v representing an extracellular volume value, and obtaining normalized intensity values of each grid point of the calibration map based on the maximum intensity; assigning one of multiple categories to each grid point based on a degree of change in concentration values between initial time point Ti and initial time point T 2 ; and adjusting the calibration map such that grid points of a first category for grid points with a relatively high degree of change and grid points of a second category for grid points with a relatively low degree of change are approximately equally represented in the calibration map.
  • the assigning of the one of the three categories may be done, for example, by coloring or shading the grid point.
  • Tj and T 2 may be set such that the first classification is assigned to approximately 75% of grid points representing malignant tissue.
  • the concentration values of the contrast agent are measured by a CT imaging machine.
  • the visual representation of the malignancy classification that is output may be color-coded image data.
  • the visual representation may be a voxel (volume pixel) representation, such that each pixel represents a volume of tissue.
  • the region of lung tissue may be evaluated based on the spatial distribution of malignant tissue in the visual representation.
  • registration can be used to correct for shifting of the region of tissue in the obtaining of the concentration values. Also, in outputting of the visual representation smoothing based on surrounding pixels may be used to provide a more satisfactory image.
  • Fig. 1 shows a diagram illustrating a relationship between concentration of contrast agent and signal strength.
  • Fig. 2 illustrates enhancement expressed in Hounsfield Units representing signal strength as a function of time after contrast agent injection at a specified dose.
  • Fig. 3 shows a diagram for classifying a pixel (assigning one of three colors) based on wash-out rate, according to an aspect of the invention.
  • Figs. 4a-4b show a flow diagram for preparation of a calibration map, according to an aspect of the invention.
  • Fig. 5 is a schematic diagram of a tissue classifier.
  • Figure 6 is a chart illustrating the variation of contrast agent concentration (y-axis) as a function of time (x-axis) for three lung tissue profiles, and for blood.
  • Figs. 7a and 7b show examples of calibration charts with different maximum K values according to an aspect of the present invention.
  • the type of contrast agent used and its dose will depend on the type of imaging device from which imaging data is gathered.
  • the relationship between the image data received, such as signal intensity and contrast agent concentration will depend on the type of contrast agent used. This information might be available from the company that provides the contrast material, or it can be independently measured as described below for the contrast agent Iopromide -Ultravist 300 (Shering).
  • HU units Hounsfield Units measuring signal intensity S(t) are converted to Ultravist 300 concentration units (ml ultravist 300 solution/liter saline).
  • concentration C(t) of contrast material in ml per 1
  • S(t) p + qC (t) where ? and q are parameters to be determined.
  • Enhancement, E(t) is defined as the difference in signal intensities before and after contrast material injection:
  • the experimental factor that converts HU units to contrast material concentration units can be determined by preparing tubes with different concentrations of Ultravist 300 in normal saline. The tubes can then be scanned by the CT.
  • C in ml Ultravist 300 per 1 saline
  • C may be in the range of 0 to 2%> (20 ml per 1) which is approximately the concentration in the blood after the injection.
  • Figure 1 shows the signal intensity S of a central ROI obtained as part of the research study referred to herein, showing a calibration curve of iopromide (Ultravist 300 Shering) in saline solution, where the concentration of 1 ml/1 corresponds to 0.1% iopromide in saline solution, hence, lOml/1 corresponds to 1%.
  • the dose of 1.5 ml/kg in a 70 kg patient corresponds to ⁇ 20ml/l , about 2% in blood.
  • the present inventors calibrated the CT scanner as part of a research study.
  • An explanation of the research study will illuminate aspects of the present invention.
  • Thirty- four patients 22 men and 12 women; mean age 64 years; age range 47-82 years) were recruited from patients referred to the radiology department either from the Thoracic
  • the contrast agent for the CT was Iopromide (Ultravist 300; Schering) at a dose of 1.5 ml/kg, delivered through the antecubital vein at a rate of 3 ml/sec using an automatic injector (En Vision CTTM). The patients were instructed to hold their breath following maximal expiration during the scanning, to decrease movement.
  • the contrast agent Iopromide (1 ml containing 0.623 g Iopromide) was selected for this study because it is a non-ionic water-soluble X-ray contrast medium with low osmotic pressure and better general tolerance compared to ionic contrast media.
  • the contrast agent Iopromide (1 ml containing 0.623 g Iopromide) was selected for this study because it is a non-ionic water-soluble X-ray contrast medium with low osmotic pressure and better general tolerance compared to ionic contrast media.
  • Iopromide has a molecular weight of 791.12 d (compared to 936 d of
  • Iopromide is extremely hydrophilic and prevented from entering the intracellular lumen. Therefore, like Gd-DTPA, following IV administration iopromide is very rapidly distributed in the extracellular space, the half-life being 3 minutes, with an elimination half-life in patients of normal kidney function approximating 2 hours, irrespective of the dose (only 1.5%> of the dosage is excreted in feces).
  • the inventors recorded the signal intensity, S, of a central ROI in the aorta before contrast administration and at a selected time point after contrast injection.
  • the inventors in the research study used the relation between HU and concentration units of
  • Fig. 2 illustrates enhancement (as defined in Eq. 2) in the aorta as a function of time after Iopromide (ultravist 300) injection at a dose of 0.15ml/kg.
  • the decay in the enhancement followed eq. 3 using the concentration to enhancement conversion (equation 2).
  • the exchange of contrast material between the intravascular and extravascular extracellular volumes in each pixel of the tumor is dependent upon two parameters: the influx transcapillary transfer constant k in and the efflux transcapillary constant k ep .
  • the latter constant is equal to the outflux transcapillary constant k out divided by the effective extracellular volume fraction v e .
  • the division by v e stems from the fact that the contrast material cannot enter the cells and is therefore leaking solely to the extracellular interstitial spaces.
  • kj n and v e are two independent parameters that determine the contrast enhancement time course.
  • k; n depends on both the blood flow rate and the vessel permeability.
  • P vessel permeability
  • S surface area per unit volume
  • FIG. 6 is a chart illustrating the variation of contrast agent concentration (y-axis) as a function of time (x-axis) for three lung tissue profiles, and for blood (dotted curve), with two time points T t and T 2 .
  • the upper solid curve is an example of a profile for malignant tissue, which is near its peak at Ti.
  • the lower most solid curve is an example of non- malignant tissue.
  • Fig. 4 shows a flow diagram as an example of a method for setting the parameters for data collection and creating a calibration map.
  • concentration of the contrast agent varies with time as a function of two variables of the system assigned here with the letters K and v.
  • the pharmacokinetics parameters define the contrast agent change with time in the blood.
  • the variable K defines microvascular permeability which estimates the capacity of blood vessels to leak out the tracer.
  • the variable v defines the fraction of extracellular volume which estimates the amount of free space in a tissue. For each grid point in a 2 dimensional grid of K and v, a pixel of dimension of 0.01 units of K and 0.01 units of v is defined at blocks 38, 40, 53 and 55.
  • the program starts at block 30 and gets inputs of the time points, to, ti and t 2 , system and measurement parameters and the range of K and the range of v values between their minimum and maximum values in block 31.
  • the signal values are fed to signal data interface 1-11 of the tissue classifier 1-1 from the CT imaging device 1-3 or other such imaging device.
  • the entire tissue classifier 1-1, or one or more portions or modules thereof may be physically or logically integrated with the CT imaging device 1-3 as a software, hardware, firmware, or other such component or module of the CT imaging device 1-3, or the tissue classifier 1-1, or one or more portions thereof, may be connected via a wired or wireless connection with the CT imaging device
  • the data may be saved in database 1-2.
  • Database 1-2 may be physically or logically integrated with the tissue classifier 1-1 and/or with the CT imaging device or may be connected thereto via a wired or wireless connection.
  • Controller 1-17 may control the input/output of the tissue classifier 1-1, its interface with the CT imaging device 1-3 and with a human operator, and may control overall functioning of the tissue classifier 1-1.
  • Concentration value generator 1-12 converts the signal intensities to concentration values, according to a function (or lookup table) of the type shown in Fig. 1.
  • the CT or imaging device may already feed the concentration values to the tissue classifier 1-1, instead of just the signal strength data.
  • Calibration map generator 1-13 starts from pixel (K min, v min) in block 32 to calculate I(t 0 ), I(t ⁇ ), I(t 2 ) in block 33, estimating how the concentration varying with time I(t) depends on K and v, and on other system parameters.
  • the determined or calculated I(tl) and I(tO) are used to calculate for each pixel Intensity (K, v) as shown in block 34, which represent wash-in initial rate, at least for malignant tissue.
  • the calibration map generator 1-13 controls a search for the pixel that has maximum intensity (blocks 35 to 40) and proceeds through all the pixels loop- wise returning to block 33 and going again through the steps 34 to block 40 until it reaches the pixel with maximum K and maximum v.
  • the pixel with maximum intensity is identified and intensity is calculated for all pixels (K, v).
  • the program proceeds to calculate for each pixel starting from pixel (K min, v min) block 43 a normalized intensity, normalized relative to the maximum intensity, as shown at block 44.
  • the pixel with maximum intensity is assigned a maximum value for intensity N.
  • N can be 1, 2, 3 or any number such as, 8, 64, 256 (computer numbers), etc. depending on the demands of the system.
  • pixel classifier 1-15 calculates the wash-out pattern for each pixel starting from pixel (K min, v min) until it reaches pixel (K max, v max) and codes with color hue each pattern as shown in blocks 45 to 54.
  • color or hue of the pixel shows the change in intensity between ti and t 2 for that pixel.
  • the intensity I(t 2 ) is less than I(t ⁇ )
  • the color hue is red
  • the reverse holds the color is blue
  • the intensity is equal or close to equal, it is green.
  • Most malignant tissue will be shown as red pixels, and most non-malignant tissue will be shown as blue.
  • Visual representation output 1-16 produces in block 56 of Fig. 4b as the output a calibration map of K, v for the selected to, ti, t 2 and system and measurement parameters.
  • the output consists of a calibration map of the two variables K and v ranging between K min, v min to K max, v max for a specific set of time points and the other inputs.
  • Each pixel in this map with specific K, v values has a color hue and a color intensity.
  • 7a and 7b are examples of color-coded (in black and white) calibration maps with the red region shown on the left lower portion with more pixels in the higher K, lower v range, and blue region shown on the right upper portion with more pixels in the lower K, higher v range.
  • the calibration map is not satisfactory, for example, if it is excessively slanted toward one color hue, new time points are chosen in a direction to correct the calibration map and bring it to a more satisfactory balance from a color distribution standpoint. Accordingly, in subsequent iterations, the program cycles through the steps in the flow diagram again using the new inputs until a satisfactory calibration map is obtained, which sets the selected time points and system parameters.
  • a satisfactory calibration map is defined by reaching a certain distribution of the colors or of the colors and color intensities.
  • a satisfactory map can be a map that divides the K- v plane, or volume between the three colors to approximately three equal areas, namely, approximately a third of the pixels in the calibration map are red, a third are green and a third are blue.
  • new time points ti and t may be selected to arrive at a calibration map such that the red color is assigned to approximately 75%> of grid points representing malignant tissue.
  • MFH metastatic Malignant Fibrous Histiocytoma; Ly - Lymphoma; Breast met. - Breast metastasis; MM - Multiple Myeloma; SFT - Solitary Fibrous Tumor.
  • Another difference is that through coloring of the central pixels in the malignant tumor, most of the colored pixels of the benign lesion are on its contour. Coloring of the tumor's borders is usually the result of movement of the tumor between t 0 and t, . Since the enhanced tumors are surrounded by normal lung tissue containing air (black in CT), the difference in enhancement intensity in a pixel between t 0 and t, can be large on behalf of movement of the tumor to an area of normal lung tissue (or vice versa). This occurs mainly along the contour of the tumor.
  • CT image moved between different time points, mostly due to thoracic breathing movement.
  • the amount of movement in the z direction was evaluated by looking at sequential slices of the tumor in the three different time points on the screen, and forming triplets of the same slice at the three time points.
  • Movement in the x-y direction was initially evaluated by putting a semi-transparent slice on top of its corresponding slice at a different time point and moving it until the best fit was found. The amount of movement in the x and y direction was recorded, and inserted into specially developed software which shifted all the pixels in the slice by the assigned amount. Later in the course of our study, an automatic registration algorithm was developed. Movement in the x-direction ranged between 0-20 pixels and in the y-direction between 0-12 pixels, both with a median of 2 pixels. This algorithm does not take into account rotation, angulation, shrinkage or enlargement of the tumor, which we ignored and presumed minimal.
  • registration may be accomplished in several known ways, if it is to be performed at all, without departing from the spirit of the present invention.
  • the inventors also tested the application of "smoothing"; the color hue and intensity of each pixel was assigned after taking into account the values of the eight surrounding pixels as well.
  • smoothing is used based on four or more surrounding pixels to provide for an enhanced visual representation. It will be understood that several known smoothing methods may be used to perform smoothing according to this embodiment of the invention.
  • Tables 2 and 3 show statistical analysis of the study results.
  • Table 2 contains the benign results.
  • Table 3 contains the malignant results.
  • Table 3 Malignant Tumors from the Upper Left to the Lower Right Corner.
  • the present study shows that the method disclosed herein can distinguish readily between a benign and malignant SPN using the 3TP-CT method.
  • the gross differences include: higher fraction of colored tumor pixels in the malignant as opposed to the benign tumors; higher percentage of the tumor's pixels being colored in red in the malignant versus the benign tumors; higher color-intensity in the malignant versus the benign tumors.

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Abstract

L'invention concerne une méthode de classification de malignité et un support permettant de classifier une région du tissu pulmonaire. La classification consiste à déterminer des points temporels T1 et T2 mesurés à partir de l'injection d'un agent de contraste. T1 représente un point temporel d'accumulation pour le tissu pulmonaire malin auquel une première valeur de concentration de l'agent de contraste injecté est sensiblement égale à une valeur maximale ou voisine d'une valeur maximale pour la concentration de l'agent de contraste injecté dans la région du tissu pulmonaire. On obtient les valeurs de concentration chez le patient de l'agent de contraste pour la région du tissu pulmonaire aux points temporels T1 et T2, une classification de malignité pour cette région du tissu pulmonaire étant réalisée par comparaison des valeurs de concentration d'échantillon obtenues avec un profil de malignité prédéterminé. Une représentation visuelle de la classification de malignité de cette région du tissu pulmonaire est alors produite en sortie.
PCT/IB2005/001252 2004-04-08 2005-04-08 Methode de detection, de diagnostic et de pronostic du cancer du poumon faisant appel a trois points temporels WO2005096694A2 (fr)

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CA002561168A CA2561168A1 (fr) 2004-04-08 2005-04-08 Methode de detection, de diagnostic et de pronostic du cancer du poumon faisant appel a trois points temporels
EP05747932A EP1743279A4 (fr) 2004-04-08 2005-04-08 Methode de detection, de diagnostic et de pronostic du cancer du poumon faisant appel a trois points temporels
US10/593,887 US7693320B2 (en) 2004-04-08 2005-04-08 Three time point lung cancer detection, diagnosis and assessment of prognosis
IL178472A IL178472A0 (en) 2004-04-08 2006-10-05 Three time point lung cancer detection, diagnosis and assessment of prognosis

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IL178472A0 (en) 2008-03-20
EP1743279A2 (fr) 2007-01-17
CA2561168A1 (fr) 2005-10-20
US7693320B2 (en) 2010-04-06
WO2005096694A3 (fr) 2007-01-18
EP1743279A4 (fr) 2010-09-01

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